Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment

Abstract

Purpose: Outcome in acute myeloid leukemia (AML) worsens with age, at least in part because of higher treatment-related mortality (TRM) in older patients. Eligibility for intensive AML treatment protocols is therefore typically based on age as the implied principal predictor of TRM, although other health- and disease-related factors modulate this age effect.

Patients and methods: We empirically defined TRM using estimated weekly hazard rates in 3,365 adults of all ages administered intensive chemotherapy for newly diagnosed AML. We used the area under the receiver operator characteristic curve (AUC) to quantify the relative effects of age and other covariates on TRM in a subset of 2,238 patients. In this approach, an AUC of 1.0 denotes perfect prediction, whereas an AUC of 0.5 is analogous to a coin flip.

Results: Regardless of age, risk of death declined once 4 weeks had elapsed from treatment start, suggesting that patients who die during this time comprise a qualitatively distinct group. Performance status (PS) and age were the most important individual predictors of TRM (AUCs of 0.75 and 0.65, respectively). However, multicomponent models were significantly more accurate in predicting TRM (AUC of 0.83) than PS or age alone. Elimination of age from such multicomponent models only minimally affected their predictive accuracy (AUC of 0.82).

Conclusion: These data suggest that age is primarily a surrogate for other covariates, which themselves add significantly to predictive accuracy, thus challenging the wisdom of using age as primary or sole basis for assignment of intensive, curative intent treatment in AML.

Fig 1.

Survival analyses. (A) Kaplan-Meier survival analyses of overall survival of 1,127 patients enrolled onto Southwest Oncology Group (SWOG) trials from 1986 to 2009 and 2,238 patients treated at MD Anderson Cancer Center (MDA) from 1995 to 2009 for newly diagnosed acute myeloid leukemia (non–acute promyelocytic leukemia). (B) Plots of probability of death in specific week given that patient was alive at beginning of week (weekly hazard) for patients enrolled onto SWOG trials or treated at MDA. (C-E) Weekly hazard plots for all patients enrolled onto SWOG trials or treated at MDA, stratified by age ([C] ≤ 60, [D] 61-70, [E] > 70 years of age). Slopes of changes in weekly mortality tended to decrease after week 3 in SWOG and week 4 in MDA for patients age 60 years or younger and those older than age 70 years; for patients age 61 to 70 years, slopes tended to decrease after week 4 in SWOG and after week 3 in MDA, respectively.

Fig 2.

Prediction of early death. Importance of individual covariates to predict treatment-related mortality (TRM) using χ² values with (A) inclusion or (B) exclusion of age. Importance evaluated with Wald χ² statistic minus predictor's degrees of freedom (df). Covariates with larger χ² values considered more important in predicting TRM. Covariates listed on y-axis in order of χ² value, with highest values at top and lowest at bottom. In both panels, performance status (PS) is most important single variable in predicting TRM. Several variables, including hemoglobin (HGB) and fibrinogen, were among least important for both models. AML, acute myeloid leukemia; LDH, lactate dehydrogenase.